PDF(Pubmed)
Abstract：
BACKGROUND: Genetic variants in the coding region could directly affect the structure and expression levels of genes and proteins. However, the importance of variants in the non-coding region, such as microRNAs (miRNAs), remain to be elucidated. Genetic variants in miRNA-related sequences could affect their biogenesis or functionality and ultimately affect disease risk. Yet, their implications and pleiotropic effects on many clinical conditions remain unknown.
METHODS: Here, we utilised genotyping and hospital records data in the UK Biobank (N = 423,419) to investigate associations between 346 genetic variants in miRNA-related sequences and a wide range of clinical diagnoses through phenome-wide association studies. Further, we tested whether changes in blood miRNA expression levels could affect disease risk through colocalisation and Mendelian randomisation analysis.
RESULTS: We identified 122 associations for six variants in the seed region of miRNAs, nine variants in the mature region of miRNAs, and 27 variants in the precursor miRNAs. These included associations with hypertension, dyslipidaemia, immune-related disorders, and others. Nineteen miRNAs were associated with multiple diagnoses, with six of them associated with multiple disease categories. The strongest association was reported between rs4285314 in the precursor of miR-3135b and celiac disease risk (odds ratio (OR) per effect allele increase = 0.37, P = 1.8 × 10-162). Colocalisation and Mendelian randomisation analysis highlighted potential causal role of miR-6891-3p in dyslipidaemia.
CONCLUSIONS: Our study demonstrates the pleiotropic effect of miRNAs and offers insights to their possible clinical importance.
METHODS: Here, we utilised genotyping and hospital records data in the UK Biobank (N = 423,419) to investigate associations between 346 genetic variants in miRNA-related sequences and a wide range of clinical diagnoses through phenome-wide association studies. Further, we tested whether changes in blood miRNA expression levels could affect disease risk through colocalisation and Mendelian randomisation analysis.
RESULTS: We identified 122 associations for six variants in the seed region of miRNAs, nine variants in the mature region of miRNAs, and 27 variants in the precursor miRNAs. These included associations with hypertension, dyslipidaemia, immune-related disorders, and others. Nineteen miRNAs were associated with multiple diagnoses, with six of them associated with multiple disease categories. The strongest association was reported between rs4285314 in the precursor of miR-3135b and celiac disease risk (odds ratio (OR) per effect allele increase = 0.37, P = 1.8 × 10-162). Colocalisation and Mendelian randomisation analysis highlighted potential causal role of miR-6891-3p in dyslipidaemia.
CONCLUSIONS: Our study demonstrates the pleiotropic effect of miRNAs and offers insights to their possible clinical importance.
摘要：
背景：编码区的遗传变异可直接影响基因和蛋白质的结构和表达水平。然而,非编码区变异的重要性，如microRNAs（miRNAs），还有待阐明。miRNA相关序列中的遗传变异可能影响其生物发生或功能，并最终影响疾病风险。然而，它们对许多临床病症的影响和多效性作用仍然未知.
方法：这里，我们利用UKBiobank(N=423,419)中的基因分型和医院记录数据,通过表型全关联研究,调查miRNA相关序列中346个遗传变异与广泛临床诊断之间的关联.Further,我们通过共定位和孟德尔随机化分析检验了血液miRNA表达水平的变化是否会影响疾病风险.
结果：我们在miRNAs的种子区鉴定了6个变异体的122个关联，miRNAs成熟区的9个变异体,和前体miRNA中的27个变体。这些包括与高血压的关联，血脂异常,免疫相关疾病，和其他人。19种miRNA与多种诊断相关，其中6种与多种疾病有关。据报道，miR-3135b前体中的rs4285314与乳糜泻风险之间的相关性最强（每个效应等位基因增加的比值比（OR）=0.37，P=1.8×10-162）。共定位和孟德尔随机化分析强调了miR-6891-3p在血脂异常中的潜在因果作用。
结论：我们的研究证明了miRNAs的多效性，并为其可能的临床重要性提供了见解。
方法：这里，我们利用UKBiobank(N=423,419)中的基因分型和医院记录数据,通过表型全关联研究,调查miRNA相关序列中346个遗传变异与广泛临床诊断之间的关联.Further,我们通过共定位和孟德尔随机化分析检验了血液miRNA表达水平的变化是否会影响疾病风险.
结果：我们在miRNAs的种子区鉴定了6个变异体的122个关联，miRNAs成熟区的9个变异体,和前体miRNA中的27个变体。这些包括与高血压的关联，血脂异常,免疫相关疾病，和其他人。19种miRNA与多种诊断相关，其中6种与多种疾病有关。据报道，miR-3135b前体中的rs4285314与乳糜泻风险之间的相关性最强（每个效应等位基因增加的比值比（OR）=0.37，P=1.8×10-162）。共定位和孟德尔随机化分析强调了miR-6891-3p在血脂异常中的潜在因果作用。
结论：我们的研究证明了miRNAs的多效性，并为其可能的临床重要性提供了见解。
